The kidney and liver are the two major sites of HDL holoparticle uptake and catabolism. Cubilin, a multiligand cell surface receptor, localized on the apical surface of renal epithelium cells has been proposed to mediate renal HDL catabolism. Cubilin is an extrinsic membrane protein and megalin has been suggested to function as a coreceptor in cubilin mediated HDL cellular uptake. A canine model intracellular processing of the cubilin protein in the renal proximal tubule. The objective of the present study was to determine the role of cubilin in apolipoprotein A-I (apoA-I) HDL metabolism in the cubilin dysfunctional canine (CD) model. Autologous 125I-apoA-I HDL was injected in CD and control dogs. Plasma lipids in the CD dogs were as follows: TC 135 mg/dl, Trig 54 mg/dl, HDL 115 mg/dl, and apoA-I 110 mg/dl and were similar to controls. By FPLC< apoA-I was distributed in HDL1 and HDL2 in controls while apoA-I was primarily located in HDL2 in the CD model. The fractional catabolic rate (FCR) in the CD model was similar (0.196 d-1) to controls (0.169+/-0.005 d-1). Urine was collected in 3 CD dogs as well as throughout the kinetic study and the presence of intact apoA-I was assessed by SDS-polyacrylamide gel (PAGE) and TCA precipitation. Negligible amount (<4%) of intact apoA-I or 125I-apoA-I in the kinetic study were present on SDS-PAGE in the urine. By TCA precipitation, <4% of the urine 125I was present as intact apoA-I in the precipitate. In summary: 1) The catabolism of apoA-I on HDL was similar in control and the cubilin dysfunctional canine animal model. 2) A greater percentage model. 3) Virtually no intact apoA-I was present in the urine in the CD canines. Conclusions: Renal catabolism of apoA-I can occur independent of cubilin and significant quantities of intact apoA-I are not present in the urine of the CD canine animal model. These combined results indicate that a separate receptor system independent of cubilin may effectively catabolize HDL in the kidney.